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9.
Survival of APPNL/F
-KI x Calpastatin (CS)-KO
mice
CS deficiency did not affect the survival of APPNL-F
KI
mice at least up to 20 months.

10.
1. Role of inflammation
2. Role of various proteases
3. Effect of Aβ vaccination
4. Effect of ApoE4
5. Effect of the environmental
enrichment
6. Effect of various diets and
supplements
7. Others (Tau, Dynamin, Arc, etc.)
Major issues to be re-addressed

15.
Finally, we should compare our mice with APPNL/NL
mice
crossbred with mutant presenilin 1 (PS1) knockin mice24
,
which also overproduce Aβ42 without overexpressing
APP. These APP/PS1 double knockin mice are
comparable to the APPNL-F/NL-F
mice in this respect. There
are, however, two major difficulties that limit the utility
of the double knockin mice. The first is that they are
doubly homozygous: crossing them with other mutant
mice is practically impossible. To our knowledge, no
researchers have done so as yet. The second is that
presenilin mutations affect biological processes other
than γ-cleavage of APP25
; no perfect negative controls
exist. It should also be noted that the function(s) of PS1
may, at least in part, differ between humans and mice26
.